Thiopurine Methyltransferase in Humans:
Development and Tissue Distribution

Pacifici, Gian Maria; Romiti, P.; Giuliani, L.; Rane, Anders

doi:10.1159/000457495

Cited by 39 publications

(16 citation statements)

References 8 publications

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“…Our previous work on the development of conjugation pathways in humans has shown that the activities of the cytosolic enzymes, such as acetyl transferase [7], glutathione Stransferase [8], sulphotransferase(s) [9,10] and thiopurinemethyltransferase [11], are 2-3 times lower in fetal than adult liver. In con trast, the activities of uridine diphosphate glucuronyl transferase [12,13] and thiomethyltransferase [14] are 6-108 times lower in fetal than adult liver.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work on conjugation path ways has shown that some cytosolic enzymes such as acetyl transferase [7], glutathione Stransferase [8], sulphotransferase [9,10] and thiopurine methyltransferase [11] are better developed in fetal life compared to the pre dominantly microsomal enzymes such as glucuronyl transferase [12,13] and thiomethyltransferase [14], In order to ascertain whether such a differential development pat tern holds true for other non-microsomal enzymes as well, we measured the rate of for mation of hippuric acid from benzoic acid, which is believed to be catalysed by a mito chondrial enzyme system, namely glycine transferase [3][4][5]15], in human fetal and adult livers and kidney.…”

Section: Introductionmentioning

confidence: 99%

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Conjugation of Benzoic Acid with Glycine in the Human Fetal and Adult Liver and Kidney

Pacifici¹,

Mogavero²,

Giuliani³

et al. 1991

Dev Pharmacol Ther

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The rate of hippuric acid formation was measured in the homogenates obtained from 26 specimens of human adult liver, 9 specimens of human mid-gestational fetal liver, 5 specimens of human adult kidney and 11 specimens of human mid-gestational fetal kidney. The average (pmol/min/mg tissue ± SD) rate of hippuric acid formation was 322 ± 99 (adult liver), 7.6 ± 3.6 (fetal liver), 284 ± 117 (adult kidney) and 6.4 ± 6.7 (fetal kidney). One third of the fetal livers and kidneys studied were inactive in the formation of hippuric acid. These findings indicate that the conjugation of carboxylic acid with glycine is poorly developed in the mid-gestational human fetus. The kinetics of the formation of hippuric acid were studied in 3 fetal and adult livers and also in 3 fetal kidneys and in 3 specimens of the cortex and medulla of adult kidneys. The transformation of the data into Eadie-Hofstee plots generated straight lines in fetal and adult livers and kidneys. The Michaelis-Menten constant for the formation of hippuric acid (mean ± SD, mM) was 43.4 ± 6.6 (adult liver), 27.3 ± 10.1 (fetal liver), 33.3 ± 6.1 (adult renal cortex), 34.7 ± 11.3 (adult renal medulla) and 15.3 ± 3.5 (fetal kidney). The maximum velocity of the reaction (mean ± SD, pmol/min/mg tissue) was 204 ± 47.8 (adult liver), 6.0 ±1.3 (fetal liver), 199 ± 40.7 (adult renal cortex), 24.2 ± 16.9 (adult renal medulla) and 6.4 ± 1.8 (fetal kidney). The inhibitory effect of 8 drugs containing a carboxylic acid group on the rate of hippuric acid formation was studied in 3 adult livers. Salicylic acid and diflunisal were the most powerful as inhibitors. Ibuprofen, furosemide and sodium valproate were weak inhibitors, whereas ketoprofen, naproxen and captopril did not inhibit the formation of hippuric acid. The IC(50) values (mean ± SD) of salicylic acid and diflunisal on the rate of hippuric acid formation were 0.19 ± 0.05 and 1.18 ± 0.19 mM, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conjugation of Benzoic Acid with Glycine in the Human Fetal and Adult Liver and Kidney

Pacifici¹,

Mogavero²,

Giuliani³

et al. 1991

Dev Pharmacol Ther

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“…Therefore, the developmental pattern of TMT is tissuedependent and the adult kidney seems to be an important site of méthylation. Such a consideration holds true for thiopurinemethyltransferase, the activity of which is twice as high in kidney than in liver [13].…”

Section: Mean ± Sdmentioning

confidence: 99%

Thiol Methyltransferase in Humans: Development and Tissue Distribution

Santerini²,

Giuliani³

et al. 1991

Dev Pharmacol Ther

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Thiol methyltransferase (EC 2.1.1.9, TMT) activity was measured with 2-mercaptoethanol in the microsomal fraction of 12 placenta and 31 fetal and 33 adult liver specimens. TMT activity (nmol/min incubation/mg protein; mean ± SD) was 0.61 ± 0.25 (placenta), 0.74 ± 0.45 (fetal liver), and 4.51 ± 2.29 (adult liver). TMT activity was also measured in extrahepatic tissues and it was about one order of magnitude lower in fetal lungs, kidney and intestine as compared with the fetal liver. A similar distribution pattern was also observed in adult tissues except that in the kidney TMT activity was one third of the hepatic one. Studies of enzyme kinetics showed that fetal and adult hepatic TMT obeyed non-Michaelis-Menten kinetics when 2-mercaptoethanol was the varying substrate. Average values of Km for the higher and lower affinity phases were 0.03 and 14.05 mmol/l, respectively (fetal liver) and 0.005 and 14.57 mmol/l, respectively (adult liver). This paper shows that TMT develops prenatally and its distribution pattern is consistent with that of other microsomal enzymes, being preferentially associated with the liver both in the human fetus and in adult subject.

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“…TPMT is a cytoplasmic enzyme present in liver, kidney and brain cells, red and white blood cells and bone marrow cells that catalyses the S-methylation of 6-MP and 6-TG [Remy 1967;Weinshilboum et al, 1978;Van Loon and Weinshilboum 1982;Woodson and Weinshilboum 1983;Weinshilboum 1989;Pacifici et al, 1991;Szumlanski et al, 1992;Van Loon et al, 1992;McLeod et al, 1995;Coulthard et al, 1998] with S-adenosyl methionine (SAM) as a methyl donor [Remy 1963;Elion 1967]. Although extensively studied and present already in primitive species [Otterness et al, 1985;Salavaggione et al, 2005], the physiological role of TPMT is not clear and a defective enzyme has not been linked to any disease .…”

Section: Tpmt Pharmacogeneticsmentioning

confidence: 99%

Thiopurines in Inflammatory Bowel Disease - The Role of Pharmacogenetics and Therapeutic Drug Monitoring

Lindqvist¹,

Hindorf²,

Almér³

et al. 2006

CPG

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Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing inflammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol derivative and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complex and individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thiopurine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatase polymorphisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased interest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to identify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment.

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Thiopurine Methyltransferase in Humans: Development and Tissue Distribution

Cited by 39 publications

References 8 publications

Conjugation of Benzoic Acid with Glycine in the Human Fetal and Adult Liver and Kidney

Conjugation of Benzoic Acid with Glycine in the Human Fetal and Adult Liver and Kidney

Thiol Methyltransferase in Humans: Development and Tissue Distribution

Thiopurines in Inflammatory Bowel Disease - The Role of Pharmacogenetics and Therapeutic Drug Monitoring

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